This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. U.S. Persistent smoking behavior (Le., failure or difficulty in remaining abstinent) has continued to be a major public health concern. Accumulating evidence suggests that genetic factors may playa role. Perhaps most compelling is recent research demonstrating that smokers who carry specific polymorphisms in genes related to CNS dopamine signaling (e.g., DRD2, SLC6A3) exhibit higher levels of persistent smoking behavior. The underlying behavioral mechanisms linking these polymorph isms to persistent smoking behavior are not yet known. One possibility stems from recent findings from our lab, in which carriers of a Taql RFLP polymorphism ("A1") at DRD2 and a 40bp VNTR at SLC6A3 ("9-repeat") exhibited elevated self-reported cigarette craving responses following exposure to smoking cues. While these findings are largely consistent with the preclinical literature on dopamine's role in subserving responses to appetitive cues, to date, relations between these polymorphisms, cue-induced craving, and CNS functioning have not been examined. In this pilot study, we propose to explore the possibility that smokers who are carriers of the DRD2-A 1 and SLC6A3-9-repeat polymorph isms will not only exhibit higher self-reported craving, but also higher levels of activity in brain regions found to be associated with dopamine transmission (Le., anterior cingulate gyrus [ACG], amygdala [Amy], nucleus accumbens [NAc], ventral striatum [VS], orbitofrontal cortex [OFC], temporal lobe [TL], and insula [Ins]) during exposure to video smoking cues. Purpose: To test the hypothesis that carriers of the DRD2-A 1 and SLC6A3-9-repeat polymorphisms will exhibit elevated fMRI BOLD activity in the ACG, Amy, NAc, VS, OFC, TL and Ins, during exposure to smoking-related video cues, compared to noncarriers.